Coenzyme q10 containing proliposome and preparation thereof

ABSTRACT

A coenzyme Q 10  and ceramide-containing preliposome, and pharmaceutical preparations and cosmetics containing the same. The preliposome can further comprise other lipid components. A granular and lyophilized solid-preparation is produced by lyophilization or spray drying. Then, the coenzyme Q 10 -containing proliposome is obtained by adding water in the said solid-preparation and shaking. Transdermal absorption of coenzyme is improved together with the effect of coenzyme Q 10  in cosmetics and the stability of coenzyme Q 10  and liposome, which facilitate the formulation of cosmetics.

FIELD OF THE INVENTION

The present invention relates to the fields of pharmaceutics andcosmetics. More specially, the present invention relates toCoQ₁₀-containing preliposomes, and more particularly, relates to thepreparation method and the application of CoQ₁₀-containing preliposomeswhich contain spongiamine.

BACKGROUND OF THE INVENTION

CoQ₁₀ (conenzymeQ₁₀, ubidecarenone) is a kind of a liposoluble quininecompound, which has the same character as a vitamin. The prominentfunction of CoQ₁₀ is anti-oxidation and cleaning free radicals CoQ₁₀ isone of the most important functional components used in many anti-agingproducts at parent. It has been proved experimentally that CoQ₁₀ canaccelerate the metabolism of skin, accelerate the transport of cellularrespiration chain and ATP production of facial and hand skin.Simultaneously, CoQ₁₀ can inhibit oxidation of the skin lipid, andconsequently nourish and activate the skin. It is reported that bodyslimming lotions and UV expert creams which contain CoQ₁₀ have obviouseffects on preventing the formation of furrows, whitening thecomplexion, increasing the elasticity of the skin and so on. CoQ₁₀ notonly protects the skin, but also prevents and cures skin diseases ofhuman beings. It has been experimentally proven that CoQ₁₀ has obvioustherapeutic effects on photoallergy, dermatitis, hair-lose, bedsores,ulcers, wounds of the skin, hyperpigmentation and so on. Because themolecular structure of CoQ₁₀ has an unsaturated double bond, CoQ₁₀ isextremely unstable and is easy to oxidize and becomes decomposed by theoxygen and light in the air. In addition, heating or contacting CoQ₁₀with metal ions will accelerate its decomposition. As a result, thecontent of CoQ₁₀ in products becomes decreased, and the activity ofCoQ₁₀ is quickly lost, adversely affecting the quality and actual effectof the products. In addition, CoQ₁₀ is a liposoluble compound, whichmakes it difficult to mix with the water-soluble cosmetics. Theforegoing disadvantages of CoQ₁₀ extremely restrict the development andapplication of CoQ₁₀.

Liposomes are composed of hydrophilic bursa bubbles which consist oflecithoid double molecular layers. Liposomes have characteristics thatimprove the stability of drug encapsulation, facilitate the percutaneonsabsorption of drugs, prolong the time of drug action, control the drugtargeting at local pathological parts of the body, and decrease the sideeffects of drugs. Thus, as drug carriers, liposomes have been widelyused in pharmaceutics and cosmetics. CoQ₁₀ liposomes could improve thestability of drugs, facilitate the percutaneous absorption of drugs, andincrease the water-solubility of drugs. But generally being a kind ofliposome suspension solution, CoQ₁₀ has obvious shortcomings in thestability. The reasons are as following:

1. As colloidial particulates, liposomes are a kind of unstablethermodynamic system which is easy to congregate, fuse and sedimentate,and the oxidation decompose of the lecithoid causes leakage of theencapsulation drug into the aqueous solution, etc., resulting in theinstability of the liposome.

2. The instability of the structure of CoQ₁₀ makes drugs more instablein the water.

3. The ratio of CoQ₁₀, liposome suspension and drug content is generallyfixed; however, the required content of CoQ₁₀ differs in differentcosmetics. Thus, it is not convenient to mix CoQ₁₀ liposome suspensionswith cosmetics which contain CoQ₁₀.

So it is necessary to find a kind of liposome preparation which isconvenient, flexible, easy to mix with cosmetics which contain CoQ₁₀, inorder to make the liposomes and drugs more stable, and storable for along periods of time.

DISCLOSURE OF THE INVENTION

An object of present invention is to overcome the shortcomings of CoQ₁₀and common CoQ₁₀ liposome, and to supply a kind of CoQ₁₀-containingpreliposomes which contain spongiamine. The present invention willincrease the stability of CoQ₁₀ and liposomes and make the mixing ofcosmetics more flexible and convenient.

The CoQ₁₀-containing preliposomes made according to the presentinvention are a kind of solid preparation which are the granular andlyophilized. Before using, water is added to the CoQ₁₀-containingpreliposomes. After hydration and surging, the CoQ₁₀-containingpreliposomes can become CoQ₁₀-containing liposomes.

The structure of the CoQ₁₀-containing preliposomes of the presentinvention contain spongiamine at a concentration at 0.1%˜20% (W/W).Spongiamine can further facilitate the percutaneous absorption andimprove the effect of CoQ₁₀ in cosmetics.

The CoQ₁₀-containing preliposomes which contain spongiamine according tothe present invention are prepared by the following methods andprocesses.

1) CoQ₁₀, spongiamine and other lipid components are melted by heatingor are dissolved by proper organic solvent(s) so that a lipid solutionis made,

2) A fluidized bed can be used to spray the abovementioned lipidsolution on an underlay which is suspended in the middle of thefluidized bed. The organic solvent is volatilized, and CoQ₁₀-containingpreliposomes which contain spongiamine is obtained,

3) Make the lipid solution mentioned in step 1) and water solution whichcontains an underlay by known methods such as a membrane dispersionmethod or a melt method or an infuse method to obtain CoQ₁₀-containingliposomes which contain the underlay,

4) Make the CoQ₁₀-containing liposomes which contain an underlay byfreeze drying or spray drying, or wiping off the moisture to obtainCoQ₁₀-containing preliposomes which contains spongiamine.

The CoQ₁₀-containing preliposomes of the present invention contain CoQ₁₀at a concentration at of 0.2˜40% (W/W). After restoring by adding water,the concentration of the CoQ₁₀ is 0.1˜20% (W/W).

Suitable organic solvents that can be used according to the presentinvention include dichloromethane, trichloromethane, ether and ethanol.

The concentration of underlay used according to the present inventioninvolved in the CoQ₁₀ preliposomes which contain spongiamine is 1˜80%.

Underlays that can be used according to the present invention areselected from one of the following materials: mannitol, glucose,sorbitol, sucrose, lactose, fucose, sodium chloride andpolyvinylpyrrolidone.

The lipid components that can be used according the present inventioninclude spongiamine and at least one of the following components:cholesterol, soy lecithin, yolk lecithin, hydrogenated lecithin, DSPC,DPPP, poloxamer, DMPC and non-ionic surfactant hire Brij.

The materials used in according to the present invention are allcommercially available.

The CoQ₁₀-containing preliposomes which contain spongiamine according tothe present invention not only have the same merit as the commonliposomes in that they increase the stability of the drugs, facilitatethe percutaneous absorption of drugs, and prolong the time of drugaction In addition, the CoQ₁₀-containing preliposomes which containspongiamine according to the present invention have the followingmerits:

1. The increased stability of CoQ₁₀-containing liposomes allow forlonger storage times.

Because the the preliposomes are solid drugs, they overcome theshortcomings that the common liposomes have, such as congregating,sedimentating, fusing, leaking and so on.

2. The stability of the CoQ₁₀ is increased.

Because the the preliposomes are solid drugs, the present invention canbe used to make unstable more stable in the solid stats than in theliquid state.

3. The percutaneous absorption of the CoQ₁₀ is increased.

The structure of the liposomes containing spongiamine according to thepresent invention facilitate the percutaneous absorption of drugs.

The CoQ₁₀-containing liposomes of the present invention can be mixedwith other components at at random making them easier and moreconvenient to formulate into cosmetics.

Generally, for cosmetics which contain liposomes there is a certainrange of the liposome volume. If the contains of liposomes exceed therange, characteristics of the cosmetics will be affected, such asviscosity, flow property, viscosity, the content of the active componentand so on. Furthermore, certain cosmetics require different amounts ofthe CoQ₁₀. Before use, water can be added to the CoQ₁₀-containingpreliposomes which contain spongiamine according to the presentinvention on demand, so as to provide liposomes which have differentdrug contents to meet different cosmetic prescriptions.

EXAMPLES Example 1

In this example, 120 g of CoQ₁₀, 50 g of spongiamine. 50 g of yolklecithin, 100 g of cholesterol, 100 g of sucrose, were combined withenough PBS (pH 7.4) to produce a volume of 1000 ml.

The CoQ₁₀, spongiamine, yolk lecithin and cholesterol from the aboveprescription were put into a triangle flask, heated to cause fusion, andstored in a water bath at 80° C. for further use. 800 ml of PBS (pH 7.4)was used to dissolve the 140 g of sucrose. The dissolved solution wasfiltered and heated in a water bath to reach the same temperature withthe liposome solution. The sucrose solution was mixed with the liposomesolution by surging and cooled. Enough PBS (pH 7.4) was added to produce1000 ml of the mixed solution A high pressure homogeneous management (50MPa of high pressure, 10 MPa of low pressure) was used to obtain aliposome suspension solution. After spray drying, a fluidCoQ₁₀-containing preliposomes which contained spongiamine was obtained.

Example 2

In this example, 30 g of CoQ₁₀, 50 g of spongiamine, 30 g of soylecithin, 100 g of cholesterol, 40 g of poloxamer F₅₈, 200 g of glucose,and 200 ml of chloral, were combined with enough PBS (pH 7.4) to producea volume of 1000 ml.

The CoQ₁₀, spongiamine, soy lecithin, poloxamer F₆₈ and cholesterol fromthe above prescription were put into a 1000 ml rocked flask and thechloral was used to dissolve the lipid components. The resulting mixturewas subject to membrane evaporation in a water bath at 25˜40° C. to makethe lipid form a membrane layer at the bottom of the rocked flask. 800ml of PBS (pH 7.4) was used to dissolve the 200 g of glucose. Thesolution was filtered and added to the flask containing the lipidmembrane for hydration thereof using surging. Enough PBS (pH 7.4) wasadded to produce 1000 ml of mixed solution which was subject toultrasonic treatment (output 4, duty cycle 50%, time 10 mins) to producea liposome suspension solution. After freeze drying (temperature at −50°C. the degree of vacuum is 50 millitorr), a kind of looseCoQ₁₀-containing preliposomes which contain spongiamine was obtained.

Example 3

In this example, 50 g of CoQ₁₀, 50 g of sponge 60 g of hydrogenatedlecithin, 40 g of cholesterol, 50 g of poloxamer F₆₈, and 80 g offucose, 200 ml of ether, were combined with enough PBS (pH 7.4) toproduce a volume of 1000 ml.

The CoQ₁₀, spongiamine, hydrogenated lecithin, poloxamer F₆₈ andcholesterol from the above prescription were put into a 500 ml oftriangle flask and the ether was added to dissolve the lipid componentsfor further use. 800 ml of PBS (pH 7.4) was used to dissolve the 80 g offucose. The fucose solution was filtered and put into the triangle flaskwhich was stored in a water bath at 30˜60° C., and mixed round bymagnetic force at the speed of 200˜1000 rpm. After the organic solventwas evaporation a liposome suspension solution was obtained and freezedried (temperature at −50° C., the degree of vacuum is 50 millitorr) toproduce a kind of loose CoQ₁₀-containing preliposomes which containspongiamine.

Example 4 Test of Stability

Samples of the three batches of CoQ₁₀-containing preliposomes whichcontain spongiamine and a common CoQ₁₀-containing liposomes (theliposomes suspension before drying) were stored separately at atemperature of 40° C. and at a relative humidity level of 75%. After 0,1, 2 and 3 months, High Performance Liquid Chromatography (BPLC) wasused to test the content of CoQ₁₀ in the preliposomes and the commonliposomes. The content of 0 month CoQ₁₀ in the preliposomes and thecommon liposomes was used as 100% to compare the content of drug atother times with the above mentioned content of CoQ₁₀, and calculate thepercent content of drug as the time goes by.

Table 1 lists the stability comparing results of the content of CoQ₁₀ inthe preliposomes and the common liposomes. TABLE 1 The change percent ofthe content of CoQ₁₀ (%) Time (mo) 0 1 2 3 Common 100.00 93.32 88.0383.50 liposomes Preliposomes 100.00 99.86 99.53 98.76

The results show that the content of the drug contained in the commonliposomes decreased along with the time while the content of the drugcontained in the preliposomes did not decrease along with the timesignificantly. This indicates that the CoQ₁₀-containing preliposomeswhich contain spongiamine could evidently improve the stability ofdrugs.

1. CoQ₁₀-containing preliposomes, which contain spongiamine in theliposome structures.
 2. CoQ₁₀-containing preliposomes according to claim1, wherein the preliposomes are granular and a lyophilized solid. 3.CoQ₁₀-containing preliposomes of according to claim 1, wherein thepreliposomes contain CoQ₁₀ at a concentration of 0.2˜40% (W/W). 4.CoQ₁₀-containing preliposomes according to claim 1, wherein thepreliposomes contain spongiamine at a concentration of 0.1˜20% (W/W). 5.CoQ₁₀-containing preliposomes according to claim 1, further containinganother lipid component.
 6. A method of preparing the CoQ₁₀-containingpreliposomes of claim 1 which comprises: prepare a lipid solution by oneof: a) melting CoQ₁₀ and spongiamine: and b) dissolving CoQ₁₀ andspongiamine in an organic solvent: and applying the lipid solution to anunderlay to produce the CoQ₁₀-containing preliposomes which containspongiamine,
 7. The method of claim 6, wherein the underlay comprises atleast one of mannitol, glucose, sorbitol, sucrose, lactose, fucose,sodium chloride and polyvinylpyrrolidone.
 8. A pharmaceuticalcomposition that comprises the CoQ₁₀-containing preliposomes of claim 1.9. A cosmetic composition that comprises the CoQ₁₀-containingpreliposomes of claim
 1. 10. CoQ₁₀-containing preliposomes according toclaim 5, wherein the another lipid component comprises at least one ofcholesterol, soy lecithin, yolk lecithin, hydrogenated lecithin, DSPC,DPPP, poloxamer, DMPC and a non-ionic surfactant.
 11. The method ofclaim 6, wherein the lipid solution is applied to the underlay using afluidized bed and the organic solvent is evaporated in the fluidizedbed.
 12. The method of claim 6, wherein the lipid solution is applied tothe underlay by one of a membrane disperse process, a melt process andan infuse process.
 13. The method of claim 6, wherein after the lipidsolution is applied to the underlay the resulting mixture is subject toat least one of a freeze drying process, a spray drying process and aprocess of wiping moisture off the underlay.
 14. The method of claim 13,wherein the underlay comprises at least one of mannitol, glucose,sorbitol, sucrose, lactose, fucose, sodium chloride andpolyvinylpyrrolidone.
 15. CoQ₁₀-containing preliposomes according toclaim 2, wherein the preliposomes contain CoQ₁₀ at a concentration of0.2˜40% (W/W).
 16. CoQ₁₀-containing preliposomes according to claim 2,wherein the preliposomes contain spongiamine at a concentration of0.1˜20% (W/W).
 17. CoQ₁₀-containing preliposomes according to claim 2,further containing another lipid component.
 18. CoQ₁₀-containingpreliposomes according to claim 17, wherein the another lipid componentcomprises at least one of cholesterol, soy lecithin, yolk lecithin,hydrogenated lecithin, DSPC, DPPP, poloxamer, DMPC and a non-ionicsurfactant.